DESCRIPTION: In the US, syphilis continues to be a major problem in men who have sex with men, especially those infected with HIV. Studies from the pre-penicillin era documented that Treponema pallidum, the bacterium that causes syphilis, could be identified in cerebrospinal fluid (CSF) early in the course of disease in some, but not all, patients, and not every patient with syphilis developed neurosyphilis (NS). Our work has shown that high serum rapid plasma reagin titers, and HIV infection, particularly if untreated or with low peripheral blood CD4+ T cells, predict increased NS risk. We hypothesize that host immune defects in peripheral T. pallidum clearance underlie development of NS, which may be exacerbated by HIV-induced immunosuppression. In this proposal we return to the basic immune response to syphilis to test our hypothesis: T. pallidum is cleared by activated macrophages that ingest and kill opsonized organisms. We will investigate each step in this mechanism in the peripheral blood in HIV-infected and -uninfected patients with syphilis and determine the effect on NS. The Specific Aims are: 1) Identify genetic variants that impact development of NS in HIV- infected and -uninfected patients with syphilis. We show that patients with common single nucleotide polymorphisms in TLR1, 2 and 6 genes are more likely to have NS. Hypothesis: one or more as yet unidentified rare variants have a greater effect on NS susceptibility than the TLR SNPs that we have studied; 2) Determine the relationship between the ability of monocyte-derived macrophages (MDMs) to ingest T. pallidum (macrophage function) and development of NS in HIV-infected and -uninfected patients with syphilis. We show that MDMs from normal donors differ in their intrinsic ability to ingest opsonized Nichols (laboratory) strain T. pallidum. Hypothesis: the ability of macrophages to ingest opsonized T. pallidum is a property intrinsic to the host that is impaired in patients with NS; 3) Determine whether T. pallidum strain types associated with NS resist phagocytosis. We show that patients with NS are more likely to be infected with T. pallidum tp0548 strain type f than patients without NS. Hypothesis: T. pallidum strain types associated with NS are phagocytosed to a lesser extent than strain types not associated with NS; 4) Determine the relationship between the ability of serum to opsonize T. pallidum (opsonic capacity) and development of NS in HIV-infected and -uninfected patients with syphilis. We show that, among HIV- infected patients, those with CSF abnormalities consistent with NS have significantly lower serum opsonic capacity compared to those without CSF abnormalities. Hypothesis: serum opsonic capacity is lower in patients with laboratory and clinical NS compared to those with uncomplicated syphilis; 5) Determine strain- specific opsonic capacity of antisera to T. pallidum protein Tp0548. Hypothesis: antibody to Tp0548 is opsonic and opsonic capacity differs by strain, with antisera to type f being less opsonic than antisera to other types. This work offers the potential to transform our understanding of the pathogenesis of NS.